dbSNP rs5030060: KNG1:c.930+2454C>T (chr3-186735128-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001102416.3(KNG1):c.930+2454C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 152,066 control chromosomes in the GnomAD database, including 5,213 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.23 ( 5213 hom., cov: 32)

Consequence

KNG1
NM_001102416.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.179

Publications

8 publications found

Variant links:

Genes affected

KNG1 (HGNC:6383): (kininogen 1) This gene uses alternative splicing to generate two different proteins- high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK). HMWK is essential for blood coagulation and assembly of the kallikrein-kinin system. Also, bradykinin, a peptide causing numerous physiological effects, is released from HMWK. Bradykinin also functions as an antimicrobial peptide with antibacterial and antifungal activity. In contrast to HMWK, LMWK is not involved in blood coagulation. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduces or depletes angiotensin converting enzyme 2 (ACE2), which results in an increase in levels of des-Arg(9)-bradykinin, a bioactive metabolite of bradykinin that is associated with lung injury and inflammation. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2020]

KNG1 links:

HRG-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

HRG-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KNG1	NM_001102416.3 link	c.930+2454C>T	intron_variant	Intron 7 of 9	ENST00000644859.2	NP_001095886.1	P01042-1
KNG1	NM_000893.4 link	c.930+2454C>T	intron_variant	Intron 7 of 10		NP_000884.1	P01042-2
KNG1	NM_001166451.2 link	c.822+2454C>T	intron_variant	Intron 6 of 9		NP_001159923.1	P01042-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2 link	c.930+2454C>T		intron_variant	Intron 7 of 9		NM_001102416.3	ENSP00000493985.1		P01042-1

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

35600

AN:

151948

Hom.:

5209

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0566

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.327

Gnomad ASJ

AF:

0.348

Gnomad EAS

AF:

0.220

Gnomad SAS

AF:

0.191

Gnomad FIN

AF:

0.284

Gnomad MID

AF:

0.364

Gnomad NFE

AF:

0.312

Gnomad OTH

AF:

0.271

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.234

AC:

35613

AN:

152066

Hom.:

5213

Cov.:

AF XY:

0.235

AC XY:

17474

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0564

AC:

2343

AN:

41512

American (AMR)

AF:

0.328

AC:

4999

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.348

AC:

1206

AN:

3470

East Asian (EAS)

AF:

0.220

AC:

1136

AN:

5160

South Asian (SAS)

AF:

0.192

AC:

926

AN:

4820

European-Finnish (FIN)

AF:

0.284

AC:

3000

AN:

10558

Middle Eastern (MID)

AF:

0.364

AC:

107

AN:

294

European-Non Finnish (NFE)

AF:

0.312

AC:

21226

AN:

67982

Other (OTH)

AF:

0.271

AC:

569

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1317

2634

3952

5269

6586

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

382

764

1146

1528

1910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.289

Hom.:

21018

Bravo

AF:

0.235

Asia WGS

AF:

0.214

AC:

743

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

4.0

(source)

DANN

Benign

0.81

PhyloP100

0.18

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over